rs80027572

chr21-33268417-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_000628.5(IL10RB):c.73G>A(p.Glu25Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 1,613,932 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (3 hom.)
• Consequence: IL10RB NM_000628.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.366

Genes affected

IL10RB (HGNC:5965): (interleukin 10 receptor subunit beta) The protein encoded by this gene belongs to the cytokine receptor family. It is an accessory chain essential for the active interleukin 10 receptor complex. Coexpression of this and IL10RA proteins has been shown to be required for IL10-induced signal transduction. This gene and three other interferon receptor genes, IFAR2, IFNAR1, and IFNGR2, form a class II cytokine receptor gene cluster located in a small region on chromosome 21. [provided by RefSeq, Jul 2008]

IFNAR2-IL10RB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 21-33268417-G-A is Benign according to our data. Variant chr21-33268417-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 339691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-33268417-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0027 (411/152332) while in subpopulation AFR AF= 0.00895 (372/41580). AF 95% confidence interval is 0.0082. There are 0 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL10RB	NM_000628.5	c.73G>A	p.Glu25Lys	missense_variant	2/7	ENST00000290200.7
IFNAR2-IL10RB	NM_001414505.1	c.733G>A	p.Glu245Lys	missense_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL10RB	ENST00000290200.7	c.73G>A	p.Glu25Lys	missense_variant	2/7	1	NM_000628.5	P2

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 411 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00897

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000724 AC: 182 AN: 251456 Hom.: 0 AF XY: 0.000522 AC XY: 71 AN XY: 135908

Gnomad AFR exome AF: 0.00910

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000407 AC: 595 AN: 1461600 Hom.: 3 Cov.: 30 AF XY: 0.000355 AC XY: 258 AN XY: 727128

Gnomad4 AFR exome AF: 0.00983

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.00270 AC: 411 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74490

Gnomad4 AFR AF: 0.00895

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000546 Hom.: 0

Bravo AF: 0.00315

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000857 AC: 104

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inflammatory bowel disease 25 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -

IL10RB-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.28
Sift	Benign	0.18	T
Sift4G	Benign	0.64	T
Polyphen		0.054	B
Vest4		0.16
MVP		0.70
MPC		0.38
ClinPred		0.0041	T
GERP RS		-0.040
Varity_R		0.20
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: -23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80027572; hg19: chr21-34640722; COSMIC: COSV99063474; COSMIC: COSV99063474;